RU2449998C2 - Gsk-3 inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula

, wherein R_B is specified in:

while R₃, R₄, R'₂, R'₃, R'₄, R'₅, and R'₆ represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

Description

The invention relates to enzyme inhibitors, more specifically urea derivatives as kinase-3β glycogen synthase inhibitors, GSK-3, methods for producing such compounds, pharmaceutical compositions containing them, and their use for the treatment and / or prevention of diseases in the development of which GSK-3 is involved, such as Alzheimer's disease or non-insulin-dependent diabetes mellitus.

State of the art

The search for new therapeutic agents in recent years has been greatly facilitated by a better understanding of the structure of enzymes and other biomolecules associated with the diseases under study. One of the important classes of enzymes subjected to comprehensive research are protein kinases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-related events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, considerable efforts have been made in drug chemistry to search for protein kinase inhibitors effective as therapeutic agents.

Kinase-3 glycogen synthase (GSK-3) is a serine / threonine protein kinase composed of α and β isoforms, each of which is encoded by a separate gene (Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kinnel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)). Threonine / serine kinase kinase-3 glycogen synthase (GSK-3) plays a major role in various receptor-related signaling pathways (Double, B.W. Woodgett, J.R. J. Cell Sci. 2003, 116: 1175-1186). Improper regulation of these pathways is considered the main event in the development of some common human disorders, such as type II diabetes (Kaidanovich O., Eldar-Finkelman H., Expert Opin. Ther. Targets, 2002, 6: 555-561), Alzheimer's disease ( Grimes CA, Jope RS, Prog. Neurobiol. 2001, 65: 391-426), CNS disorders such as manic-depressive psychosis and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich KP, Luo J., Rubie EA, Tsao MS, Jin O., Woodgett J. Nature 2000, 406: 86-90). These diseases can be caused or can lead to the malfunctioning of certain cell signaling pathways in which GSK-3 plays a role.

GSK-3 was found to phosphorylate and modulate the activity of several regulatory proteins. These proteins include glycogen synthase, which is a rate-limiting enzyme necessary for glycogen synthesis, Tau microtubule-associated protein, genetic transcription factor β-catenin, translation initiation factor elF2B, as well as ATP-citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB and CEPBα. This diversity of protein targets involves GSK-3 in many aspects of cellular metabolism, growth, differentiation, and development.

Currently, inhibition of GSK-3 may represent a viable strategy for the development of new medical substances for the treatment of such incurable diseases (Martinez A., Castro A., Dorronostro I., Alonso M., Med. Res. Rev., 2002, 22; 373- 384) by simulating insulin, dephosphorylation of tau and treatment of amyloid or modulation of transcription, respectively.

In the current state of the art, certain compounds containing a urea group are already described as having GSK-3 inhibitor properties. These are, for example, the following publications: WO03 / 004472, WO03 / 004475, WO03 / 089419. Each of these publications refers to a very large number of compounds characterized by the Markush formula, which is a large and complex structure, which complicates their preparation and increases the possibility of reactivity of the compounds. In particular, these compounds belong to structural subgroups, such as substituted thiazole compounds and heterocyclic amines. These compounds may contain, along with other groups, a functional group of urea. These compounds are generally described as having GSK-3 inhibitory effects and, therefore, potential activity in the treatment and prevention of a series of diseases associated with GSK-3, such as dementia, diabetes and mood disorders. However, none of the above publications includes information regarding the inhibition of GSK-3 by any particular compound; thus, for compounds comprising a urea functional group, the results are not shown, which really confirm any activity of these urea derivatives.

On the other hand, publication WO03 / 004478 and the article "Structural Insights and Biological Effects of GSK-3 specific ingibitor AR-A014418", J. Biol. Chem., 278 (46), 2003, consider one particular urea derivative, 4- (4-methoxybenzyl) -N '- (5-nitro-1,3-thiazol-2-yl) urea; the structure of this derivative is of course much smaller and simpler than the urea derivatives mentioned above. This derivative is described as having GSK-3 inhibitory properties and, therefore, as having potential activity for treating and / or preventing numerous conditions associated with kinase-3 glycogen synthase. However, it is unclear whether the GSK-3 inhibitory effect is due to urea or neurothiazole itself, since heterocyclic compounds have been described as exhibiting GSK-3 inhibitory properties (see, for example, the aforementioned WO03 / 089419).

Some other urea derivatives are described in connection with the treatment of neurological disorders, but in connection with completely different mechanisms of action, for example WO00 / 06156, where the urea derivatives described are described as glutamate receptor potentiators.

Thus, there is still a need to find a good GSK-3 inhibitor that is both effective and selective and has good “drug-forming” properties, i.e. good pharmaceutical properties associated with administration, distribution, metabolism and excretion. An additional advantage will be finding compounds with simple, stable structures that are easy to manufacture by conventional methods known to those skilled in the art.

Description of the invention

A group of stable small urea derivatives was found to exhibit inhibitory effects on the GSK-3 enzyme.

The use of the compounds of formula (I)

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein

R _{B is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, where aryl is selected from the group consisting of phenyl, naphthyl, phenanthryl and anthracyl, substituted or unsubstituted aralkyl, where aralkyl is benzyl, a heterocycle selected from the group consisting of azepines, benzimidazole, benzothiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxole, thiophene, benzofuran, indazole, quinazoline, pyridazine, pyrimidine, pi azine, pyridine, isoxazole, pyrrole, pyran, -OR ₅ or -S (O) _t -R _5, wherein R _B comprises from 8 to 15 atoms selected from C, O, N and S, with the proviso that R _B is not a heterocycle substituted by a heterocycle,

R ₃ , R ₄ , R ' ₂ , R' ₃ , R ' ₄ , R' ₅ and R ' _{6 are} independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, -C (= O) R ₇ , -C (= O) OR ₈ , -C (= O) NR ₉ R ₁₀ , -C = NR ₁₁ , -CN, -OR ₁₂ , -OC ( = O) R ₁₃ , -S (O) _t -R ₁₄ , -NR ₁₅ R ₁₆ , -NR ₁₇ C (= O) R ₁₈ , -NO ₂ , -N = CR ₁₉ R ₂₀ or halogen, where R ₃ and R ₄ together can form a group = O and where any pair of R ₃ R ' ₂ , R ₃ R' ₆ , R ₄ R ' ₂ , R ₄ R' ₆ , R ' ₂ R' ₃ , R ' ₃ R' ₄ , R ' ₄ R' ₅ , R ' ₅ R' ₆ , R ₁₅ R ₁₆ , R ₁₇ R ₁₈ or R ₁₉ R ₂₀ may together form a cyclic substituent; t is 0, 1, 2, 3,

R ^{5 is} selected from hydrogen, alkyl, aryl, and heterocycle;

R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ and R _{20 are} independently selected from hydrogen, substituted or unsubstituted alkyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, halogen, for the preparation of a medicament for the treatment and / or prevention of GSK-3 mediated disease or condition where the disease or condition is selected from a group consisting of diabetes, diabetes-related conditions, chronic neurodegenerative conditions including dementia, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, boxing encephalitis, Guam’s disease complex , corticobasal degeneration, frontotemporal dementia, Gengtington's disease, AIDS-related dementia, amyotropic lateral sclerosis, acute sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar affective disorders, stimulation of the restoration of impaired functions after a stroke, cerebral bleeding, such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, , polycystic ovary syndrome, syndrome X, ischemia, brain damage, traumatic brain damage, cancer, leukopenia, Down syndrome, Levy's disease, burning, chronic inflammatory diseases, cancer and hyperproliferative diseases such as hyperplasia and immunodeficiency.

Preferred compounds are compounds in which R _B represents an aromatic group.

In a specific embodiment, R _B contains at least 10 aromatic carbon atoms.

In an additional aspect, the invention relates to a compound of the formula

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) described above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or diluent.

Preferably, the GSK-3 mediated disease or condition is selected from Alzheimer's disease, type II diabetes, depression, and brain damage.

In accordance with another aspect, the compounds of formula (I) described above can be used as reagents for biological research, preferably as a reagent for inhibiting GSK-3.

Brief Description of the Drawings

Figure 1 presents ¹ H-NMR and ¹³ C-NMR spectra of 1-benzyl-3-naphthalene-1-urea.

Figure 2 presents ¹ H-NMR and ¹³ C-NMR spectra of 1-benzo [1,3] dioxol-5-yl-3-benzylurea.

3 is a graph showing GSK-3 activity measured in the presence of 1-benzyl-3-naphthalen-1-urea in various concentrations. The results are shown in comparison with the control.

FIG. 4 is a graph showing GSK-3 activity measured in the presence of 1-benzo [1,3] dioxol-5-yl-3-benzylurea in various concentrations. The results are shown in comparison with the control.

DETAILED DESCRIPTION OF THE INVENTION

Urea derivatives having the formula (I) in accordance with the present invention are chemicals that unexpectedly showed good inhibitory activity against the GSK-3 enzyme, combined with good stability and low toxicity.

As indicated above, a first aspect of the present invention relates to the use of compounds of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof for the manufacture of a medicament for the treatment of diseases or conditions mediated by GSK-3. Preferably, R _B represents an aromatic group, and even more preferably, R _B contains at least 10 aromatic carbon atoms.

In a preferred embodiment, the compound of formula (I) has an aromatic group that is directly bonded to the N atom of the urea group.

In accordance with another specific embodiment, R _B is a substituted or unsubstituted naphthyl group, preferably an unsubstituted alpha naphthyl group.

Preferably, R _{B is} selected from

In a specific embodiment, R ₃ and R ₄ are H.

In another specific embodiment, R ' ₂ , R' ₃ , R ' ₄ , R' ₅ and R ' _{6 are} independently selected from hydrogen, substituted or unsubstituted alkyl, -C (= O) R ₇ , -C (= O) R ₈ , —OR ₁₂ , —NR ₁₅ R _16, or halogen, where R ₇ , R ₈ , R ₁₂ , R _15, and R ₁₆ are as defined above.

Preferably, R ′ ₂ , R ′ ₃ , R ′ ₄ , R ′ ₅ and R ′ ₆ are H.

Two preferred compounds are:

In the context of the present invention, the expression “GSK-3-mediated disease or condition” means any disease or other pathological or painful condition that is known to be mediated by GSK-3. This disease or condition can be, but is not limited to, diabetes, diabetes-related conditions, chronic neurodegenerative conditions, including dementia, such as Alzheimer's disease, Parkinson’s disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, boxing encephalitis, guam parkinsonism-dementia complex, Peak's disease, corticobasal degeneration, frontotemporal dementia, Gengtington's disease associated with STI Dementia, amyotropic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar affective disorders, stimulation of the restoration of impaired functions after a stroke, cerebral hemorrhages such as due to solitary cerebral amyloid amyloid , hair loss, obesity, hypertension, polycystic ovary syndrome, Syndrome X, ischemia, brain damage, traumatic brain damage, cancer, lake singing, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency.

Preferably, GSK-3 is a mediated disease or condition selected from Alzheimer's disease, type II diabetes, depression and brain damage.

In accordance with further aspects of the invention, it relates to a compound of the formula

and its use as a medicine.

Another aspect of the present invention is a pharmaceutical composition comprising a compound as defined above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or diluent; preferably said composition is for oral administration. Preferably, diseases or conditions that can be treated with said pharmaceutical composition can include, but are not limited to, diabetes, diabetes conditions, chronic neurodegenerative conditions, including dementia, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, boxing encephalitis, guam complex parkinsonism-dementia, Peak's disease, corticobasal regeneration, frontotemporal dementia, Gengtington’s disease, AIDS dementia, amyotropic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, stimulating the restoration of impaired functions after a stroke, cerebral bleeding, such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, damage brain traumatic brain damage, cancer, leukopenia, Down syndrome, Levy's disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases such as hyperplasia and immunodeficiency.

Another aspect of the invention relates to a method for treating or preventing GSK-3-mediated diseases or conditions with a GSK-3 inhibitor, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as described above or a pharmaceutical compositions based on it.

In another aspect, the invention relates to the inhibition of GSK-3 activity in a biological sample by compounds of formula (I), by a method comprising contacting a biological sample with a GSK-3 inhibitor of formula (I). The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; enzyme preparations suitable for in vitro analysis; biopsy material obtained from mammals, or extracts thereof; blood, saliva, urine, feces, seminal fluid, tears or other body fluids or their extracts. Thus, in one aspect, the invention is directed to the use of compounds of formula I as reagents for biological assays, namely as reagents for inhibiting GSK-3.

In the above definition of compounds of formula (I), the following terms have the indicated meanings.

“Alkyl” refers to a straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms, not saturated, having one to eight carbon atoms, which is attached to the rest of the molecule by a single bond, for example methyl, ethyl, n-propyl, isopropyl , n-butyl, tert-butyl, n-pentyl, etc. Alkyl radicals may optionally be substituted with one or more substituents, such as halogen, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

“Alkoxy” refers to a radical of the formula —OR _a , where R _a is an alkyl radical described above, for example, methoxy, ethoxy, propoxy, etc.

“Alkoxycarbonyl” refers to a radical of the formula —C (O) OR _a , where R _a is the alkyl radical described above, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.

“Alkylthio” refers to a radical of the formula —SR _a , where R _a is an alkyl radical described above, for example methylthio, ethylthio, propylthio, etc.

“Amino” refers to a radical of the formula —NH ₂ , —NHR _a , —NR _a R _b , where R _a and R _b are independently the alkyl radicals described above.

"Aryl" refers to phenyl, naphthyl, indenyl, phenanthryl or anthracyl radicals, preferably phenyl or naphthyl radicals. The aryl radical may optionally be substituted with one or more substituents, such as hydroxy, mercapto, halogen, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as described herein.

“Acyl” refers to a radical of the formula —C (O) —R _c and —C (O) —R _d , where R _c is the alkyl radical described above and R _d is the aryl radical described above, for example acetyl , propionyl, benzoyl and the like.

“Aroylalkyl” refers to an alkyl group substituted with —R _a —C (O) —R _d , where R _a is the alkyl radical described above and R _d is the aryl radical described above. Preferred examples include benzoylmethyl.

“Carboxy” refers to a radical of the formula —C (O) OH.

"Cycloalkyl" refers to a stable 3-10 membered monocyclic or bicyclic radical, saturated or partially saturated, which consists only of carbon and hydrogen atoms. Unless otherwise specifically indicated in the specification, the term “cycloalkyl” also includes cycloalkyl radicals optionally substituted with one or more radicals, such as alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

"Halogen" refers to bromine, chlorine, iodine or fluorine.

“Heterocycle” refers to heterocyclic radicals. A heterocycle refers to a stable 3-15 membered ring, which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 4-8 membered ring with one or more heteroatoms, more preferably a 5- or 6-membered ring with one or more heteroatoms. For the purposes of the invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; also the nitrogen, carbon and sulfur atoms in the heterocyclic radical may optionally be oxidized; a nitrogen atom may optionally be quaternized; and the heterocyclic radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, benzodiazole, thiodiazole, thiodiazole, thiodazole, thiodazole, thiodazole, pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrazole, pyran.

Mentioned substituted groups in the compounds of the present invention relate to a specific group which may be substituted at one or more accessible positions by one or more suitable groups, for example, halogen, such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; azido; alkanoyl, such as a C _1-6 alkanoyl group, such as acyl and the like; carboxyamido; alkyl groups comprising groups having from 1 to 12 carbon atoms or from 1 to 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups, including groups having one or more unsaturated bonds and from 2 to 12 carbon atoms or from 2 to 6 carbon atoms; alkoxy groups having one or more oxygen bonds and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups, including groups having one or more thioether bonds and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; alkylsulfinyl groups, including groups having one or more sulfinyl bonds and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; alkylsulfonyl groups, including groups having one or more sulfonyl bonds and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; aminoalkyl groups, such as groups having one or more N atoms and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; unsubstituted cycloalkyl wherein cycloalkyl is as described above; unsubstituted aryl, where cycloalkyl is as described above, namely phenyl or naphthyl; and aralkyl, such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substituted position independently of the others.

Unless otherwise stated, the compounds of the invention are considered to include compounds that differ only in the presence of one or more isotope enriched atoms. For example, compounds having the present structures, with the exception of replacing hydrogen with deuterium or tritium or replacing carbon with ¹³ C or ¹⁴ C enriched carbon or ¹⁵ N-enriched nitrogen, are within the scope of this invention.

The term "pharmaceutically acceptable salts, derivatives, solvates, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate or any other compound which, when administered to a recipient, is capable of forming (directly or indirectly) the compound described herein. However, it should be appreciated that pharmaceutically unacceptable salts also fall within the scope of the invention, as they may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.

For example, pharmaceutically acceptable salts of the compounds described herein are synthesized from the parent compounds that contain basic or acidic groups by conventional chemical methods. Typically, such salts, for example, are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of the corresponding base or acid in water, or an organic solvent, or a mixture thereof. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. Examples of salts of added acids include salts of inorganic acids, such as, for example, hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, and salts of organic acids, such as, for example, acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates and para-toluenesulfonates. Examples of added alkali salts include inorganic salts, such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, and organic alkali salts, such as, for example, ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, triethanolamine salts , glucamine and basic amino acids.

Derivatives or prodrugs are particularly advantageous, increasing the bioavailability of the compounds of the invention when they are administered to a patient (for example, by allowing an orally administered compound to be more rapidly absorbed into the blood), or improving the target delivery of the parent compound to the body (e.g., to the brain or lymphatic system) relative to the parent condition.

Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrugs" is used in the broadest sense and separates derivatives that are converted in vivo to compounds of the invention. Such derivatives can be easily obtained by specialists in the field of technology and include, depending on the functional groups present in the molecule, and without limitation, the following derivatives of the presented compounds: esters, amino acid esters, phosphate esters, metal salts of sulfonate esters, carbamates and amides. Examples of well-known methods for preparing a prodrug of this active compound are known to those skilled in the art and can be found, for example, in the Textbook of Drugdesign and Discovery, Taylor & Francis (April 2002).

The compounds of the invention may be in crystalline form, both in free form and in the form of a solvate (e.g. hydrates), and it is intended that both forms are within the scope of the present invention. Solvation methods are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or chemically pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity with the exception of conventional pharmaceutical additives, such as a solvent and carriers, and not including material considered toxic at a normal dosage level. The purity levels of the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment, the purity of the compound of formula (I) or its salts, solvates and prodrugs is greater than 95%.

Compounds of the present invention, characterized by the above formula (I), may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (e.g., Z, E). Individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

Compounds of formula (I) as defined above can be prepared by available synthetic methods, for example, by reacting the following compounds:

in a suitable solvent, such as N, N-dimethylformamide, dimethyl sulfoxide, dioxane, dichloromethane or tetrahydrofuran, at a temperature ranging from +20 to + 150 ° C.

One preferred pharmaceutically acceptable form is a crystalline form, including such a form of a pharmaceutical composition. In the case of salts and solvates, additional ionic and solvate moieties must be non-toxic. Compounds of the invention may be in different polymorphic forms, it is understood that the invention includes all such forms.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) compositions for oral, topical or parenteral administration.

In a preferred embodiment, the compositions are in oral form. Suitable dosage forms for oral administration may be tablets and capsules and may contain conventional additional substances known in the art, such as binders, for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium salt starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

Solid compositions for oral administration can be prepared by conventional methods of mixing, filling or tabletting. Repeated mixing operations can be used to distribute the active agent in compositions using large amounts of fillers. Such operations are common in the art. Tablets can, for example, be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular an enteric coating tablet.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in an appropriate dosage form. Suitable additional substances may be used, such as bulking agents, buffering agents or surfactants.

Mentioned formulations will be prepared using standard methods, such as those described or indicated in the Spanish or American Pharmacopoeias and similar reference texts.

Administration of the compounds or compositions of the present invention may be carried out by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the patient's convenience and the chronic nature of many diseases to be treated.

Typically, the effective amount administered of a compound of the invention depends on the comparative effectiveness of the selected compound, the severity of the treatable disorder, and the weight of the patient. However, the active ingredients are usually administered one or more times a day, for example 1, 2, 3 or 4 times a day, in normal daily doses in the range of 0.1 to 1000 mg / kg / day.

The compounds and compositions of the invention can be used together with other drugs for the combined treatment. Other drugs may form part of a single composition or be presented as a separate composition for simultaneous or non-simultaneous administration.

In the following, the invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope described in the claims.

Examples

Obtaining compounds of formula II

The compounds of formula II of the present invention are prepared by reacting a suitable isocyanate with a suitable amine to obtain the corresponding urea, as described above.

EXAMPLE 1

Obtaining 1-benzyl-3-naphthalene-1-ylurea

0.44 ml (4 mmol) of benzylamine is reacted with 0.58 ml (4 mmol) of 2-isocyanatonaphthalene in dichloromethane at room temperature overnight:

The resulting white precipitate was filtered off and washed with diethyl ether. 1.18 g of a white powder with a molecular weight of 276 is obtained. The corresponding ¹ H-NMR and ¹³ C-NMR spectra are shown in FIG. They indicate that the white compound is 1-benzyl-3-naphthalen-1-ylurea.

EXAMPLE 2

Preparation of 1-benzo [1,3] dioxol-5-yl-3-benzylurea

0.44 ml (4 mmol) of benzylamine is reacted with 654.5 mg (4 mmol) of 5-isocyanatobenzo [1,3] dioxole in dichloromethane at room temperature overnight:

The resulting white precipitate was filtered off and washed with diethyl ether. Obtain 1 g of a white powder with a molecular weight of 276. The corresponding ¹ H-NMR and ¹³ C-NMR spectra are shown in figure 2. They show that the white compound is 1-benzyl-3-naphthalen-1-ylurea.

Biological methods

Inhibition of GSK-3

The activity of GSK-3 was determined by incubating a mixture of the recombinant human enzyme GSK-3, a source of phosphate and a substrate of GSK-3 in the presence and absence of the corresponding test compound and measuring the activity of the GSK-3 mixture.

Recombinant human kinase-3β glycogen synthase was tested in 8 mM MOPS, pH 7.3, with the addition of 0.2 mM EDTA, 10 mM MgCl ₂ and 0.25 mM sodium orthovanadate in the presence of 62.5 μM phosphoglycogen synthase peptide-2 (GS-2 ), 0.5 micro-Curie γ- ³³ P-ATP and unlabeled ATP to a final concentration of 12.5 μM. The final sample volume was 20 μl. After incubation for 30 minutes at 30 ° C, aliquots of 15 μl were applied dropwise to P81 phosphocellulose paper. The filters were washed four times for at least 10 minutes each, after which the radioactivity was measured in a 1.5 ml scintillation cocktail in a scintillation counter.

GSK-3 activity values in the presence of the compounds of the present invention were measured at various concentrations, the results shown in comparison with the control are shown in FIGS. 3 and 4.

IC ₅₀ values for compounds were calculated by analyzing inhibition curves by non-linear regression using GraphPad Prism. IC ₅₀ values (concentration at which 50% inhibition of the enzyme is shown) are tabulated.

Compound IC ₅₀ 1-Benzyl-3-naphthalene-1-ylurea 17.1 1-Benzo [1,3] dioxol-5-yl-3-benzylurea 38,4

Claims (14)

1. The use of the compounds of formula (I)

or a pharmaceutically acceptable salt thereof,
where Rb represents a group selected from:

R ₃ , R ₄ , R ₂ , R ₃ , R ₄ , R ₅ ^and R ₆ are hydrogen for the manufacture of a medicament for the treatment and / or prevention of a GSK-3 mediated disease or condition where the disease or the condition is selected from the group consisting of diabetes, diabetes-related conditions, chronic neurodegenerative conditions including dementia, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, postencephalitic parkinsonism, Guam’s parkinsonism-dementia complex, Peak’s disease, court icobasal degeneration, frontotemporal dementia, Gengtington’s disease, AIDS dementia, amyotropic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar affective disorder, hair loss, obesity, hypertension, polycystic ovary syndrome, X syndrome, ischemia, brain damage, traumatic brain damage, cancer, leukopenia, Down syndrome, Levy's disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases such as prostatic hyperplasia, and immunodeficiency. 2. The use according to claim 1, in which the compound of formula (I) is a

3. The use according to claim 1, in which the compound of formula (I) is a

4. The use according to claim 1, in which the disease is Alzheimer's disease. 5. The use of claim 1, wherein the disease is progressive supranuclear palsy. 6. The use according to claim 1, in which the disease is type II diabetes. 7. The use according to claim 1, in which the disease is depression. 8. The use of claim 1, wherein the disease is brain damage. 9. The compound of the formula

10. The compound of the formula

intended for use as a medicine having GSK-3 inhibitory activity. 11. A pharmaceutical composition having GSK-3 inhibitory activity and comprising an effective amount of a compound of formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt, pharmaceutically acceptable carrier, adjuvant or diluent thereof. 12. The pharmaceutical composition according to claim 11 for oral administration. 13. The use of a compound of formula (I), as described in any one of claims 1 to 3, as a reagent for biological in vitro GSK-3 inhibition assays. 14. A method of treating or preventing GSK-3-mediated diseases or conditions with a GSK-3 inhibitor, wherein the disease or condition is selected from the group consisting of diabetes, diabetes-related conditions, chronic neurodegenerative conditions including dementia, such as Alzheimer's disease , Parkinson's disease, progressive supranuclear palsy, postencephalitic parkinsonism, Guam's Parkinsonism-dementia complex, Peak's disease, corticobasal degeneration, frontotemporal dementia, Gengtington's disease, STI D-dementia, amyotropic lateral sclerosis, multiple sclerosis, and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar affective disorder, hair loss, obesity, hypertension, polycystic ovary syndrome, X syndrome, ischemia, brain damage, traumatic brain damage, cancer, leukopenia, Down syndrome, Levy's disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases such as hyperplasia Zia and immune deficiency, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), according to claims 1-3 or a pharmaceutical composition of claim 11 or 12.

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